Rational design of a multi-target antimalarial compound with in vivo activity
- Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton Melbourne, VIC 3800.
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052.
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052.
- School of Medicine, Deakin University, Geelong Waurn Ponds Campus, Geelong, VIC 3216.
- Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD 4111.
Malaria, particularly that caused by P. falciparum and P. vivax, remains a global health concern. Artemisinin combination therapies, the gold standard of treatment, have played a major role in reducing the malaria burden. However, parasites resistant to artemisinin treatment have emerged, and are spreading rapidly. We implemented an ambitious strategy to use rational drug discovery to develop a single compound capable of inhibiting two antimalarial drug targets, the M1 and M17 aminopeptidases, both key players in the blood stage of malaria infection. This strategy was designed to improve the efficacy of a compound by taking advantage of the synergistic effect achieved by inhibiting multiple targets within the same metabolic pathway, and additionally, to reduce the capacity of parasites to generate resistance, which occurs rapidly when parasites are treated with single-target therapeutics. We discovered potent dual inhibitors of M1 and M17 that show nanomolar in vitro activity against both P. vivax and P. falciparum (including drug resistant strains). Further, in mouse models, our most potent compound is effective against P. berghei infection after oral administration (97% reduction in parasitemia). We have therefore developed a multi-target inhibitor capable of potent activity across multiple Plasmodium species, which represents an exciting lead for further development into a novel antimalarial therapeutic.